The goal of this review is to highlight recent advances in autoinflammatory disorders caused by gain-of-function mutations in the gene encoding the NLR-family CARD-containing protein 4 (NLRC4), known as NLRC4-inflammasomopathies. Three years after the discovery of the first autoinflammation in AIFEC patients, researchers have gained a better knowledge of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and intestinal epithelial cells. This discovery has led to the development of novel treatment options for AIFEC patients, such as recombinant IL-18 binding protein and anti interferon antibodies. Other symptoms previously linked to NLRP3 mutations, such as familial cold autoinflammatory syndrome and newborn onset multisystem inflammatory disease (NOMID), have recently been linked to gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has been discovered in a NOMID and an AIFEC patient, underlining the importance of atypical routes of inheritance in autoinflammatory disorders.

The NLRC4 inflammasomopathies are a developing class of autoinflammatory diseases that range from mild urticaria to NOMID and the frequently deadly illness AIFEC. Rapid case detection using biomarkers such as increased serum IL-18 concentrations and early management with tailored immunomodulatory treatments are critical methods for improving AIFEC patient outcomes.